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21 June 2012 EMA/314313/2012 Committee of Human Medicinal Products (CHMP)/ Committee of Veterinary Medicinal Products (CVMP)

Overview of comments received on Draft Guideline on

Active Substance Master File procedure

(CHMP/QWP/227/02 Rev 3 - EMEA/CVMP/134/02 Rev 3)

Interested parties (organisations or individuals) that commented on the draft document as released for

consultation.

Stakeholder no. Name of organisation or individual

1 AESGP

2 EGA

3 Synthon BV

4 APIC

5 EFPIA

Overview of comments received on Draft Guideline on Active Substance Master File

procedure (CHMP/QWP/227/02 Rev 3 - EMEA/CVMP/134/02 Rev 3)

EMA/314313/2012 /52

1. Introduction general comments

Five stakeholders have commented to this guideline as a response of the public consultation (EGA,

AESGP, Synthon BV, APIC and EFPIA). All stakeholders were located in the European Union.

Few comments were related to the revised core text of the guideline. Only these comments have been

considered by the QWP. The remaining comments have been considered by the joint CMD/QWP/EMA

ASMF drafting group.

Overview of comments received on Draft Guideline on Active Substance Master File procedure (CHMP/QWP/227/02 Rev 3 - EMEA/CVMP/134/02 Rev 3)

EMA/CHMP/CVMP/QWP/360246/2012 /52

EMA/314313/2012

Stakeholder no. General comment (if any) Outcome (if applicable)

1 -

2 The EGA welcomes the draft EMA guideline on ASMF Procedure.

In particular, the following aspects are considered improvements:

Introduction of numerous clarifications and additional details

Clarification of the scope (exclusion of biological)

Creation of a detailed list of administrative details accompanying

the submission letter

Creation of a withdrawal letter

Response to comment not applicable.

2 Regarding the ASMF numbering system, the EGA would like to

highlight three important aspects:

The detailed guidance on the procedure to obtain a number should

be available in its final form at the moment the present guideline

enters into force;

A unique numbering system will only be viable if the possibility for

several versions of the same ASMF to coexist is safeguarded as this

is a practical consequence of having several users of the same

ASMF at different stages of the registration procedure;

The new numbering system and allocation of an EU AMSF number

to a new ASMF should not delay the submission process.

A separate document is being prepared regarding the EU

numbering system for ASMFs to be used by competent

authorities. This will not affect existing numbering systems

used by ASMF holders but where relevant the comments

made will be taken into account when developing the

numbering system.

2 The draft EMA guideline touches upon several procedural aspects,

however, the possibility of worksharing by regulatory is not

addressed in details. We believe worksharing could provide relief

both for industry and regulatory authorities and that a dedicated

section highlighting this approach should therefore be introduced.

Ideally, the section should cross-refer to a separate guideline

addressing the detailed procedural aspects of ASMF assessment

worksharing. This guidance should be available in its final form at

the moment the present guideline enters into force. Worksharing of

an ASMF (unique number) should not delay the assessment of MAA

referring to the same (unique number) ASMF. It is important to

note that the timing at which the EU ASMF number will be issued

Separate documents are being prepared regarding a

proposed assessment worksharing system and the EU


authorities. The comments made will be taken into account

when developing the above systems

Overview of comments received on Draft Guideline on Active Substance Master File procedure (CHMP/QWP/227/02 Rev 3 -

EMEA/CVMP/134/02 Rev 3)

EMA/314313/2012 /52


(before or after submission) as well as the process elected for

worksharing could have an impact on the handling and assessment

of multiple parallel applications and exert an undesirable effect on

competition between applicants.

2 Although the primary users of the guideline are the MAH/applicants,

ASMF holders have an essential role to play in this process,

particularly in the compilation of information and timely interaction

with NCA/EMA and MAH/Applicant. The guideline should therefore

also reflect that it is intended to help ASMF holders in the

compilation of their ASMFs.

This comment is already reflected in the scope of this

guideline (line 59-61).

2 Veterinary: VMF holders should be able to present new VMFs in

CTD-format to have one standard template for all master files.

The guideline already foresees that it is possible for

veterinary ASMFs to be submitted in CTD-format.

2 Herbal: considerations for herbal medicines should be introduced

Not applicable.

This comment does not relate to the aim of this revision

and will hence not be adopted at this point in time. It has

been noted for any future full revision.

3 Via this comments document Synthon would like to express its view

on the proposed revision of the draft “Guideline on Active

Substance Master File Procedure”. Synthon strongly supports the

long term objective of improvement of the ASMF procedure across

the Regulatory Network and the underlying goal to have a unique

version of an ASMF for one active substance valid for the entire

EU/EEA. Sharing assessment reports of ASMFs between the various

National Competent Authorities, the EMA including all CHMP and

CVMP Members and their experts, and the Certification of

Substances Division of the EDQM is a crucial point in this aspect


proposed worksharing system for ASMF assessment to be

used by competent authorities. The comments made will

be taken into account when developing the worksharing

system.

The initiatives to improve the ASMF procedures are being

developed by the CMD, partly in response to the described

scenario where the same ASMF is licensed out in multiple

procedures in multiple Member States, resulting in

duplication of the ASMF assessment, multiple requests for



EMA/314313/2012 /52


and is fully endorsed by Synthon. Synthon is a pharmaceutical

company with a licensing out strategy for generic drug products in

Europe. API’s are both manufactured in-house and purchased

externally. Pharmaceutical companies with a licensing out strategy

are often engaged in multiple, parallel registration procedures for a

multitude of customers. Furthermore, one drug substance can be

used in multiple drug product formulations (injectables, tablets,

capsules, etc.). For this reason the revised ASMF procedural

requirements and new administrative aspects, like handling of

ASMF versions, are in particular not suitable for pharmaceutical

companies with a licensing out strategy or for ASMF holders not

directly affiliated with the MAA. Synthon would like to assist where

possible in reaching the long term objective to have a unique

version of an ASMF for one active substance valid for the entire

EU/EEA. To reach that goal some suggestions for corrections of the

proposed guideline are provided on the following pages. Key words

are facilitating harmonization of ASMF versions and prevention of

duplication of information and duplication of review by the

authorities. Please find more detailed comments below.

information, responses and divergent updates of the ASMF,

3 Administrative Details Annex

The main change to this guideline is the new annex “Administrative

Details Annex” which involves duplication of information and the

associated complication of ASMF version management in the EU.

The purpose of the “Administrative Details Annex” is to be able to

share the information among authorities.

The Active Substance Manufacturing Sites are declared in the

following documentation:

ASMF Section S.2.1

Letter of Access to the ASMF

The comment is not endorsed.

The Submission Letter and Administrative Details Form

(Annex 3) was designed to collate in one document all the

necessary information to enable NCAs/EMA to easily

identify where the same ASMF is being used in multiple

procedures and member states. This and the proposed

worksharing system will aim to reduce duplication of

assessment and requests for information by NCAs/EMA,

leading to harmonisation of the ASMF and consequently

reducing regulatory burden on the ASMF holder and the



EMA/314313/2012 /52


Application form to the MAA

MA dossier

Quality Overall Summary

In the revision of the guideline it is additionally required to repeat

this information in the “Administrative Details Annex” to the

submission letter and therewith with every response to authority

questions or with every variation. Considering the number of MAAs

handled by pharmaceutical companies with a licensing out strategy

this is an administrative burden, while the added benefit of sharing

information is questionable. Furthermore, this is requested

irrespective of the content of the deficiency questions or the

purpose of the variation. For instance the information should also

be provided when the content of the information in the

“Administrative Details Annex” remains unchanged and no ASMF

sections need to be updated.

The repetition of information is also applicable for:

ASMF holder information

ASMF holder’s active substance specifications

Both are located in defined sections of the ASMF (S2.1 and S4.1

respectively) and can be found in numerous other places.

Including this information from the ASMF in the Quality Overall

Summary and additionally in the “Administrative Details Annex” for

new submissions and with every response creates another

bureaucratic hurdle which does not result in added value to clarity

and consistency of the provided documentation that should be

associated with the Pharmaceutical Activities. Synthon proposes to

reduce the information in the “Administrative Details Annex” and

share this among authorities with the Quality Overall Summary

MAH,

It should also be noted that similar information was

requested in the previous version of the Annex 3.



EMA/314313/2012 /52


attached. Therefore please find some suggestions for rephrasing

the text of the guideline in the table: Specific comments on text.

3 Template Submission Letter

This template contains a box in which the Name of the Medicinal

Product, the Procedure Numbers and the intended Submission date

of the MAA should be stated. This information regarding the name

of the medicinal product and the respective procedure number is

already available in the Letter(s) of Access that is/are issued

specifically for this purpose and which is/are submitted to all

authorities involved in assessing the ASMF. Duplication of

information might lead to mistakes and inconsistencies in the

provided documentation and should therefore be avoided as much

as possible. The intended submission date and the EU/ASMF

reference number are often not known at the time the ASMF is

submitted, which creates complexity or repetition of sending

submission letters. Synthon would like to propose to include the

Letter of Access with the first submission of the ASMF. This is

preferred over creating another document with similar information.

Separate guidance on completing Annexes 2, 3, & 4 are

being prepared and these comments made will be taken

into account when drafting the above document.

However, it is intended that the Letter of Access is

provided only with the initial submission of the ASMF and

will be valid for subsequent updates, until revoked by the

Withdrawal of Access Letter (Annex 4).

The Submission Letter and Administrative Details Form

(Annex 3) will be provided with the initial submission, plus

response to deficiency questions, updated, etc. Therefore,

this should include information on the associated MA/MAV.

3 Comments related to ASMF versions

Especially for pharmaceutical companies that submit multiple MAA’s

per country at different time points, maintaining one unique version

of the ASMF per drug substance for the entire EU, are often

hindered by several aspects related to the revised ASMF guidance.

The difficulties with respect to ASMF versions are explained below.

Usually multiple submissions with the same ASMF are taking place

during a period of time, combining MRPs, DCPs and national

submissions. As these are reviewed by multiple authorities they

result in different sets of requirements from each MRP, DCP and





system


developed by the CMD, partly in response to the scenario

where the same ASMF is licensed out in multiple






EMA/314313/2012 /52


national submission with different timelines. This leads to diverging

ASMFs in the EU, each with a different implementation date of the

requested changes. This is unavoidably the result of having various

decentralized reviews over a longer period of time of the submitted

ASMF. In Europe there are examples of API’s for which there are 14

different versions in 27 countries.

These initiatives will aim to reduce duplication of


consequently leading to leading to harmonisation of the

ASMF across Europe.

3 The Applicant Part that is submitted as part of the ASMF to the

authorities needs to be aligned with the Applicant Part in the MAA.

When there is one MAA this can be easily achieved, but if there are

multiple MAAs it is not an easy if not impossible to align the

Applicant Parts for all MAAs. An example is the update of an ASMF

to add a test specifically for an injectable drug product. The MAA

with only the tablets dossier will be requested to update the dossier

via costly variations while the added information has no relevance

to the product (tablets) that has been approved.





system.

3 Harmonization of the ASMF to one version number throughout the

EU would also be favourable for an ASMF holder linked to multiple

MAA’s per country. However, because the large number of

registrations connected to one ASMF and the variety of drug

products that can be referring to one ASMF the costs in labour and

variation costs for both the ASMF holder and the MAAs would be

extremely high while no added value is created. For this reason

pharmaceutical companies with a licensing out strategy cannot

harmonize their ASMFs. While the guideline encourages in wording

to keep the ASMF up-to-date both the variation guideline and the

requested documentation in this ASMF guideline leads to the

opposite.





system.


developed by the CMD, partly in response to the scenario

where the same ASMF is licensed out in multiple




These initiatives will aim to reduce duplication of


consequently leading to leading to harmonisation of the



EMA/314313/2012 /52


ASMF across Europe.

3 Though ASMF holders already aim to having one unique version of

the ASMF per active substance for the entire EU, at the moment

this is only possible via the EDQM certification procedure (CEP).

This approach is only scarcely applicable as there are several

obstacles for using the certification procedure. Firstly, a CEP

request can only be applied for if a monograph is present for the

active substance. Secondly, timelines to obtain a CEP are currently

around 18 months. For these reasons the majority of the first

submissions are performed using the ASMF procedure.

In Synthon’s view, a centralized review (and approval) of the ASMF

could be implemented in line with the current EDQM certification

procedure with a defined renewal of the approved ASMF. This would

also facilitate dossier maintenance while the EDQM certification

procedure reduces the number of variations considerably, which is a

major obstacle for pharmaceutical companies with a licensing out

strategy. Such centralized approach would also reduce the number

of assessments by the National Competent Authorities.

Further reduction of the current hurdles for dossier maintenance

could be achieved by shortening variation timelines, facilitating

regulatory requirements with variations (tightening specs, adding a

test, showing Ph. Eur. compliance) and the costs associated with

the ASMF (and subsequently Medicinal Product Dossier)

maintenance.

Not applicable.


and will hence not be adopted at this point in time. The

recommendation has been noted for further discussion.

3 Applicant Part

As mentioned above keeping the Applicant Part in the MAA

harmonized with the Open Part of the ASMF is the most challenging

aspect of ASMF maintenance for a pharmaceutical company with a

licensing out strategy and also for ASMF holders not affiliated with a

Not applicable.






EMA/314313/2012 /52


pharmaceutical company. Most changes to the ASMF affect the

Applicant Part, while the changes affecting the Restricted Part are

limited. The ASMF procedure would greatly benefit from the

simplification that only the Restricted Part is submitted to the

authorities, preferably with centralized review, while the Applicant

Part is only present in and reviewed as part of the MAA.

4 We are well aware of the fact that the proposed revision of this

guideline aims to support the recommendations and proposals

made by the CMDh ad hoc group on ASMF assessments.

We generally welcome the aspects that have been incorporated in

the current draft to accommodate the proposals from the CMDh

group, such as the revision of annex 3 and the introduction of the

withdrawal procedure for Letters of Access.

However, we would also like to take the opportunity to make some

suggestions for improvement as during the past years experience

has been gained in the industry with the 2006 draft version of the

guideline.


4 At present, the ASMF procedure is only applicable to active

substances. We would highly welcome an extension of the scope to

include intermediates (as e.g. in the US, Canada, Australia,…).

Nowadays, there is a tendency to buy starting materials and

intermediates and the NCA's request very detailed information such

as manufacturing process, critical in-process controls, etc... for

these substances. This information is considered confidential by the

producers, which may be even competitors. The same concept as

for APIs, i.e. Applicants Part and Restricted Part, can be applied

ensuring that the API-manufacturer has sufficient information to

assess potential impurities.

Not applicable.






EMA/314313/2012 /52


4 Throughout this draft guideline emphasis is laid on the fact that

there should be one unique version of the ASMF, recognizable and

identical within all member states. In our opinion this means that

this number should be assigned at a central point in Europe,

preferably before submission of the ASMF. The situation as it is

today - all member states assigning their own number (if any) - is

an undesirable situation, since it leads to additional paperwork for

both NCAs and Industry.

A separate document is being prepared regarding the EU


authorities. This will not affect existing numbering systems

used by ASMF holders but where relevant the comments

made will be taken into account when developing the

numbering system.

5 EFPIA has no major concerns with the revised guideline on Active

Substance Master File Procedure.

We have identified a number of sections of the guideline which are

unclear, and would benefit from rewording to improve clarity.




EMA/314313/2012 /52

2. Specific comments on text

Line number(s)

of the relevant

text

Stakeholder number Comment and rationale; proposed changes Outcome

15-28 1 The goal of the revision, i.e. ASMF worksharing of the

evaluation should be more precisely explained in the note

or, alternatively, reference should be made to another

document explaining this initiative.

Accepted:

The note has been revised.

17-18 4 The goal to have a unique version of an ASMF for one active

substance valid for the whole EU/EEA makes sense for both

parties, health authorities as well as industry.

It should however be recognized that at present different

versions of ASMFs may exist in the EU. For the older

national procedures question/answer rounds may have led

to different information in different member states.

Therefore there must be a realistic time frame given from

EMA in which the harmonization of all ASMF versions has to

be fulfilled, e.g. something like five years seems to be

acceptable.

Partially accepted:

Separate documents are being prepared

regarding proposed numbering and

assessment worksharing system for ASMFs

to be used by competent authorities. The

comments made will be taken into account

when developing the above documents.

17-18 4 It is unclear how the version numbering is foreseen. The

guideline should be more explicit.

Does every change to one or more of the chapters of the

ASMF lead to a change in the version number?

In our opinion applicants part and restricted part should

have independent version numbers, e.g. if the restricted

part is revised (e.g. in answer to a deficiency letter), this

should not trigger a revision of the applicants part to

prevent unnecessary variations.

Partially accepted:

A separate document is being prepared re

the EU numbering system for ASMFs to be

used by competent authorities. This will not

affect existing numbering systems used by

ASMF holders but where relevant the


when developing the numbering system.



EMA/314313/2012 /52

Line number(s)

of the relevant

text


61-82 2 Comment:

The principles applicable to the ASMF procedure should

apply for drug substances intended for use in medicinal

products for human use and for veterinary use as well as

for herbal drug substances and preparations.

Relevant guidelines quoted in the draft Guideline on ASMF

Procedure should be referenced at the end of the document

or in Chapter 3. Legal basis

Proposed change:

Please clarify the scope and update Chapter 3.

Not accepted:

Not applicable.

This comment does not relate to the aim of

this revision and will hence not be adopted

at this point in time. It has been noted for

any future full revision.

84-87 2 Comment:

Legal basis for herbal substances / preparations from lines

61-81 should be added in text from lines 84-87 if

applicable.

Proposed change:

Please update section accordingly.

Not accepted:

Not applicable.




any future full revision

89-122 2 Comment:

Information for content of herbal drugs and preparations

should be added to Chapter 4.1. Content of the Active

Substance Master File.

Additionally, subsections describing content of ASMF with

respect to use of drug substance in drug product are

proposed for clarity of the guideline:

Not accepted:

Not applicable.







EMA/314313/2012 /52

Line number(s)

of the relevant

text


General requirement (applies to all - drug substances for

human use, drug substances for veterinary use, herbal drug

substances / preparations)

Content of ASMF for drug substances used in veterinary

drug products (specific requirements)

Content of ASMF for herbal drug substances / preparations

for use in herbal drug products (specific requirements)

113-117 2 Comment:

The paragraph does not reflect the need for competent

authorities and the ASMF holder to discuss the right balance

between:

Disclosure of more information (confidential or commercially

sensitive information) in the applicant’s part and,

Necessary quality information to allow the MAH/Applicant to

fulfil its legal obligations.

Proposed change:

Please amend as follows: “In such cases, the National

Competent authorities/EMA in agreement with ASMF

holders may ask for an amendment to the AP.

Not accepted:

Not applicable.





117 4 This sentence may result in authorities requiring including

confidential information in the AP. In practice, the questions

(since "related to the AP") itself may already reveal

confidential information to the applicant.

Not accepted:

Not applicable.





121-122 4 As stated before, in our opinion this means that this

number should be assigned at a central point in Europe,

Partially accepted:




EMA/314313/2012 /52

Line number(s)

of the relevant

text


preferably before submission of the ASMF.







121-122 2 Comment:

The draft guideline reads ‘Each version of the full ASMF

should have a unique number in accordance with the

appropriate guidance’. This is then echoed in the various

annexes where EU or National ASMF numbers are to be

allocated by the NCA/EMA. As referred to in the General

comments, this guidance on ASMF numbering needs to be

available at the time of adoption of the final guideline on

ASMF procedure.

Proposed change:

None

Accepted:

The reference to appropriate guidance has

been deleted.

Separate guidance on completing Annexes

2, 3, & 4 are being prepared and these


when drafting the above document.

122 4 What does “appropriate guidance” refer to? Accepted:


been deleted.





121-122 3 Comment: The eCTD allows for updates per section, this is

tracked and documented. Also the ASMF has clear

Accepted:




EMA/314313/2012 /52

Line number(s)

of the relevant

text


granulation and could benefit from the same system of

updating one section over the entire ASMF. Updating the

entire ASMF for tightening of one specification seems

needlessly laborious.

Proposed change: Preferably each version of the full ASMF

should have a unique number in accordance with the

appropriate guidance. For ASMFs submitted via eCTD

subsections can be updated separately.

been deleted.





122 1 An example of the numbering system (as the one existing

in Rev 2 of this guideline) and/or reference to the

“appropriate guidance” number would be helpful. To which

guidance is it referred here?

Accepted:


been deleted.





122-123 2 Comment:

It is recommended that a reference or chapter on the

submission format of ASMF be added. The EGA believes the

eCTD should be the preferred and recommended format

Not accepted:

Not applicable





122

5 Comment:

“Each version of the full ASMF should have a unique

Accepted:




EMA/314313/2012 /52

Line number(s)

of the relevant

text


number in accordance with the appropriate guidance”

It is unclear to which “appropriate guidance” is referred to

here. It would be helpful to include a reference to the

relevant guidelines to avoid ambiguity.

been deleted.





130-137 1 Comment:

The text would be more appropriate in the chapter “scope”.

Proposed change:

Move the text of lines 130 – 137 to the chapter “scope”.

Not accepted:

Not applicable.





130-137 5 Comment: The text may be more appropriate in the

chapter on Scope.

Proposed change: Consider placing the text of lines 130 –

137 in the chapter on Scope.

Not accepted:

Not applicable.





139 - 146 4 The requirement „In cases where the CEP contains too little

information (e.g. stability) the National Competent

Authority/EMA may decide that additional information

should be provided in the dossier” could be a “door opener”

for inadequate requests for documents and data beyond the

CEP. The requests for additional information should be

limited to information not covered by the CEP procedure.

Proposal :

requirement „In cases where the CEP lacks certain

Not accepted:

Not applicable.







EMA/314313/2012 /52

Line number(s)

of the relevant

text


information (e.g. retest period or particle size distribution)

the National Competent Authority/EMA may decide that

additional information should be provided in the MAA”

141 2 Comment:

It is important to specifically address the situation of a

same drug substance is concerned. Additionally, it is

important to note that a single drug substance

manufacturer may have a CEP for a drug substance and an

ASMF for the same substance which is manufactured

according to alternative synthesis scheme.

Proposed change:

"an ASMF as well as to a CEP for a single active substance

from the same drug substance manufacturer of a particular

MAA/MAV."

Not accepted:

Not applicable.





144 1 Even when filing a CEP, supportive documentation e.g.

batch analysis is requested. These data being most of the

time taken from the ASMF, how can we make this fact

coincide with the requirement not to refer to both an ASMF

and a CEP?

Not accepted:

Not applicable.





147-155 2 Comment:

From the guideline(s) it is not clear when the drug

substance manufacturer should submit to applicant and

national authorities’ complete revision of the ASMF.

The EGA recommends that in general, when additional

questions from authorities are answered, the concerned

Not accepted:

Not applicable.

The submission format (e.g. eCTD, NeeS,

etc) will determine whether a complete

revision of the AP/RP, or whether updated

CTD sections, should be provided.



EMA/314313/2012 /52

Line number(s)

of the relevant

text


sections of the ASMF be revised.

148 1 Comment:

Shouldn’t this read “a copy of the latest version of the AP

(and if applicable response to a deficiency letter ....)”?

Proposed change:

“a copy of the latest version of the AP (and if applicable

response to a deficiency letter from a NCA/EMA)”

Accepted:

The comment is endorsed and the text is

revised.

148 2 Comment:

The latest version of the AP might not be consolidated and

the text should reflect that it might be complemented by

responses to deficiency letters.

Proposed change:

Please amend as follows: (including a or response to a

deficiency letter from an NCA/EMA, if relevant)

Accepted:


revised.

148 3 Comment: In line with the update per section the following

rephrasing is proposed

Proposed change:

a copy of the latest version updated sections of the AP (or

response to a deficiency letter from a NCA/EMA).

Not accepted:

Not applicable.

The submission format (e.g. eCTD, NeeS,

etc) will determine whether a complete

revision of the AP/RP, or whether updated

CTD sections, should be provided.



EMA/314313/2012 /52

Line number(s)

of the relevant

text


148 5 Comment: In regards to line 148: “- a copy of the latest

version of the AP (or response to a deficiency letter from a

NCA/EMA)”.

Would the deficiency letters pertaining to the Restricted

Part be shared with the Applicant?

Proposed change: “- a copy of the latest version of the AP

(or response to a deficiency letter from a NCA/EMA that

pertains only to the Applicant’s Part)”

Accepted:


revised.

149 4 Proposal :

Line 149 should probably read: a copy of the QOS or details

and critical summary on the latest version of the AP.

Accepted:

The comment is endorsed and the text has

been revised.

149 4 Please add “critical summary” to the Glossary.

Not accepted:

Not applicable.





149 and 343 5 Comment: Line 120-121 seem to indicate that the QOS

should be used for CTD formats, while detailed and critical

summaries are used for veterinary NtA. It is not clear if this

is the case when “QOS/details and critical summary” are

referenced in lines 149 and 343.

Accepted:

The comments line 149 and 343 is endorsed

and the text has been revised.



EMA/314313/2012 /52

Line number(s)

of the relevant

text


Proposed change: Line 149: - a copy of the QOS in CTD

format and/or details and critical summary in NtA format on

the latest version of the AP

Line 343: QOS in CTD format and/or detail and critical

summary in NtA format

150 2 Comment:

To be fully accurate, a copy of the LoA is sent to the

MAH/Applicant.

Proposed change:

Please amend text to read: “- a copy of the Letter of Access

[…]”

Accepted:


been revised.

150-155 4 “… where this letter has not been submitted earlier” This,

coupled with the fact that the LoA does not contain the

ASMF holder’s version number, implies that a new LoA is

not required each time a new version of the ASMF is

submitted. However, this should be clarified.

Partially accepted:

Separate guidance on completing and

submitting the Annexes 2, 3, & 4 are being

prepared and these comments made will be

taken into account when drafting the above

document

151-152 3 Comment: Addition of Administrative details should be

optional when no changes have been made to the

previously submitted Administrative details.

Proposed change: In addition, it is an essential requirement

that the ASMF holder should submit to all National

Competent Authorities/EMA involved in the MAA/MAV

procedure:

the ASMF accompanied by a Submission Letter, and

Administrative Details (if changed) or a Letter of Access

Not accepted:

This comment is not endorsed.

The Submission Letter and Administration

Details (Annex 3) is a single document to be

provided for every MAA/MAV using the

ASMF. This allows the NCA/EMA to establish,

maintain and confirm the regulatory history

of the ASMF.



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(first submission only), see Annex 3. This also applies to the

ASMF holder's responses to deficiency letters from a

NCA/EMA.

153 2 Amend as follows: -a copy of the latest version of the ASMF

(same as provided to the Applicant/MA Holder)

accompanied etc…. This also applies to the ASMF holder’s

responses to deficiency letters from NCA/EMA, which should

also be provided.

Partially accepted:

The comment is partly endorsed and the

text amended.

156-157 2 Comment:

Echoing our general comment on worksharing and its

application to the assessment of ASMFs, we believe that the

possibility for ASMFs for single drug substance of single

manufacturer to be submitted to each national authority

only once would help streamline the ASMF assessment and

provide relief in the procedure management for both

regulators and industry. The handling of ASMF variations

should also be considered in relevant guidelines in

connection with this worksharing approach.

Partially accepted:


regarding a proposed worksharing system

for ASMF assessment to be used by

competent authorities. The comments made

will be taken into account when developing

the worksharing system.

156-160 2 Comment:

Revision 3 of the guideline now specifies the period in which

an ASMF can be submitted by the ASMF-holder in line with

an MAA submission.

It is agreed that this should be at approximately the same

time as the MAA submission as stated, and the timeline “not

more than one month before” is considered acceptable.

However, the statement “not after the MAA submission” is

Not accepted:


The ASMF should be submitted no later than

the MA/MAV application submission,

otherwise the MA/MAV application will be

deemed invalid.



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considered unreasonable and unenforceable.

It is not clear what the consequences would be in the case

the submission of the ASMF by the ASMF holder was

delayed slightly in relation to the date of MAA submission.

We suggest that this wording is either removed, or changed

to a more manageable time limit. If it is not possible to

remove this wording, a proposal is given below.

Proposed change:

“The ASMF holder should submit the ASMF to the National

Competent Authority/EMA either for each MAA and each

MAV or only once according to national requirements. The

submission of the relevant documentation by the ASMF

holder to the National Competent Authority/EMA must be

synchronised to arrive at approximately the same time as

the MAA or the MAV i.e. not more than one month before or

and not after the MAA submission.”

157 - 158 4 Current practice is that no NCA requires submission of the

ASMF for each MAA and/or each MAV. Allowing this seems

to be in contradiction with the aim of the CMDh group.

Proposed change:

The ASMF holder should submit the ASMF to the NCA/EMA

only once.

Not accepted:

Not applicable.





159-160 4 This sentence is not clear: normally the ASMF is only

submitted once and further MAA use a new Letter of Access

to the same ASMF. Synchronization as proposed in the

guideline may be applicable for MAAs, but nor for MAVs

Not accepted:

Not applicable.





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(e.g. Type 1A Variations).

The intended submission date by the MAH is not always

known to the ASMF holder (allowances are made for this

scenario in Annex 3) , therefore the 1 month time frame is

too restrictive

Proposal :

The submission of the ASMF (first submission) and/or Letter

of Access by the ASMF holder to the NCA/EMA must be

synchronized to arrive at approximately the same time as

the MAA e.g. 2 month time frame.



159-160 4 Comment: In lines 159-160 the phrase “… not more than

one month before and not after the MAA Submission” may

be too restrictive and/or needs to be clarified. In cases of

multiple MAs referencing the same ASMF, is it expected that

the ASMF holder stagger their submissions based on the

expected MAA submissions? What if the submission date is

unknown to the ASMF holder (allowances are made for this

scenario in Annex 3)? Finally, does the one month time

period also apply to variations?

Proposed change: Clarify the one month time frame and the

expectations around submitting the ASMF.

Not accepted:


ASMFs and their updates are regularly being

submitted without an associated MA/MAV

application, contrary to the note for

guidance. The stated time frame aims to

reduce this practice.

Regular communication between the ASMF

holder and MAH is encouraged and should

facilitate meeting this timing.

161-163 2 Comment:

Lines should be omitted as this is redundant with section

145-155.

Not accepted:

Not applicable.







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163 4 Current practice is that for every letter of Access the

original is sent to the NCA/EMA, and the copy to the MAH

for inclusion in the dossier.

Proposal:

Delete "or by the ASMF holder for the product concerned"

Not accepted:

Not applicable.





164-169 2 Comment:

Lines 164-169 might be contradictory to text in lines 156-

157.

(if national authority requires submission of ASMF for each

MAA)

In addition, this section does not take into consideration the

notion of multiple versions of a unique ASMF deriving from

the multiple procedures and stages.

Proposed change:

Please amend as follows:

“Where the same active substance is used in a number of

applications for different products in one or more Member

States, the ASMF holder should submit identical

documentation to every national Competent Authority/EMA

with a clear reference to the unique number and the version

number. ASMF holders should endeavour to limit to a

minimum the number of co-existing versions.”

Not accepted:

Lines 156-157 are regarding the frequency

of submission of the ASMF to NCA’s: for

each MAA/MAH or only once, according to

national requirements (which is outside the

scope of this guideline). Lines 164-169 are

regarding the submission of the same

information to all NCA’s/EMA (one unique

ASMF version, which will be valid for the

whole EU/EEA). There are to be no co-

existing / multiple versions of one ASMF.

164-166 4 “The ASMF holder should submit identical documentation to

every NCA/EMA.” The difficulty here is maintaining identical

documentation. In a multi-customer / multi-authority

environment, a new or existing customer may submit a new

Not accepted:

The Submission Letter and Administrative

Details Form (Annex 3) will enable

NCAs/EMA to easily identify where the same



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MAA at any time so the ASMF needs to be up-to-date and

current.

Timing is a major issue in this respect. The same version of

the ASMF can be subject to multiple procedures and thus

assessments at the same time. This leads to the situation

that one procedure may be finalized, thus leading to the

request that the ASMF will be updated to include

additionally provided information, whereas the ASMF can

not be changed as a result of ongoing other procedures or

can be subject to conflicting requirements.

In addition, consideration should be given to the impact of

new applications on already-approved applications, e.g.

when more stringent specifications are required for a higher

dose product. If the ASMF has to be updated in line with

the more stringent specifications, these specifications are

then applicable to all previously approved applications

(leading to unnecessary variations).

See also comments on line 208

ASMF is being used in multiple procedures

and member states. This and the proposed

worksharing system will aim to reduce

duplication of assessment and requests for

information by NCAs/EMA, consequently

leading to leading to harmonisation of the

ASMF across Europe

166-167 4 This needs further clarification to prevent the inclusion of

superfluous information in the ASMF.

Proposal

Please add: "It is therefore important to notice that MA

specific information should not be part of the ASMF, but of

the MAA/MAV."

Not accepted:

Not applicable.





175-176 1 Proposed change:

“(CTD format section 3.2.S.4.1 and 3.2.S.4.2 or veterinary

NtA format part 2.C.1)”

Not accepted:

Not applicable.




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176 5 Comment: Recommend deleting “old human”

Proposed change: “... 3.2.S.4.2 or veterinary NtA

format .... “

Not accepted:


177-178 4 Comment: see above

Proposed change:

The AP in the MA dossier should be the most recent update

and it should be identical …

Not accepted:

Not applicable.





183-195 4 “In the case of a single supplier … the specification for the

active substance provided by the applicant/MA holder in the

MA dossier should in principle be identical to that of the

ASMF holder or the CEP holder.” This seems to contradict

line 190 where it says that “technical tests in the

specification that are relevant for the medicinal product, but

are normally not part of the specification in the ASMF (e.g.

particle size) should be part of the specification of the

applicant/MA holder.” This importance of this latter point

should be emphasised as ASMF holders are often forced by

NCA to put product-specific specifications into the ASMF.

Having these parameters in the MA dossier works when

Not accepted:

Not applicable.







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using a CEP so it should also work when using an ASMF.

The paragraph also overlooks the reality, which is that most

ASMFs are referenced by more than one MAH.

Proposal:

Where the ASMF procedure or CEP procedure is used, the

common specification for the active substance provided by

the MAH in the MAA should in principle be identical to that

of the ASMF holder or the CEP holder. Technical tests in the

specification for the API that are relevant for the production

of the Medicinal Product are part of the MA.

185 - 187 4 It seems that the Applicant/MA holder could adapt the API

specification (e.g. change “unnecessarily tight specification

limits"). This may affect the ASMF holder and any quality

commitments he has in place.

Proposal :

If the Applicant/MA holder adapts the specification he should

inform the relevant ASMF holder accordingly.

Not accepted:

Not applicable.





192-195 3 Comment: Impurities and solvents are route specific. It is

proposed to rephrase the text to specify a test to a specific

supplier.

Proposed change: In cases where there is more than one

supplier, the Applicant/MA holder should have one single

compiled specification that is identical contains

specifications for each both suppliers. It is acceptable to lay

down in the specification more than one acceptance

Not accepted:

Not applicable.







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criterion and/or analytical method for a single parameter

with the statement ‘if tested’ or designated to a specific

supplier (e.g. in case of residual solvents).

200 - 202 4 It seems that the ASMF holder should inform the

Applicant/MA holder and the National Competent

Authority/EMA regardless of the category of the change.

Proposal :

It is recommended to distinguish between (potentially) quality-

relevant and other (e.g. editorial) changes in order to avoid

mandatory information of all customers by the ASMF holder

about merely editorial changes.

Not accepted:


If the ASMF holder makes changes to the AP

or RP of the ASMF, then the AP and/or RP

have been updated. The ASMF holder has

undertaken, in their LoA, to inform the MAH

and NCA/EMA of any changes to the ASMF.

200 - 215 4 The section on changes and updates to the ASMF in the

current guideline is extremely vague and allows for different

interpretations as is evident by the publication in January

2012 of “Obligations regarding updates of Active Substance

Master Files” by the Danish Medicines Agency in which it is

recommended that changes to an ASMF be covered by a

single Type II variation. The Guideline on the Classification

of Variations makes reference to ASMFs (e.g. B.I.a.2.e)

therefore the procedures contained therein are clearly

applicable to ASMFs yet some NCA, like the Danish

Medicines Agency, do not recommend to follow these

procedures because they “often experience difficulties

concerning updates of ASMFs.” However, the impact of this

on the API industry must be taken into consideration.

Making even the smallest process change is extremely

difficult, if not impossible, for an ASMF holder in a multi-

Not accepted:

Not applicable.







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customer situation. For example, a minor process change

might be an annual reportable Type IA notification for a

manufacturer that does not use an ASMF whereas it would

be Type IB for an ASMF holder because any process change

invariably involves a change to the Restricted Part of the

ASMF and one of the conditions of the Type IA is that it

does not involve the Restricted Part. Type IB variations can

easily take over 2 years to get all the necessary approvals.

So the same change may be ‘do and tell’ for one

manufacturer but take over 2 years for another. This is

assuming that the MA holders agree to submit the

necessary variations in the first place. Often changes are

blocked because not all MA holders will agree. If, as in

Denmark, all changes to an ASMF are to be Type II, it

becomes even less likely / more prolonged. The proposed

text in the draft guidance does nothing to alleviate this

problem.

To avoid confusion, the Guideline on the ASMF Procedure

should address in more detail how changes to ASMFs should

be handled. In particular, how to handle Type IA variations

under the annual reporting procedure. It is acknowledged

that the variations regulation does not allow for the ASMF

holder themselves to submit an annual report but it is

imperative that the ASMF holder benefits from this “do and

tell” procedure. Direct contact between the authorities and

the ASMF holder is essential in order for the ASMF holder to

fulfil his responsibilities in accordance with the commitment

made in the LoA. We propose that the ASMF holder informs

both the MA holder and the authorities of a Type IA change



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at the time of implementation. The MA holder would then

include the variation in his annual report at his discretion.

203-204 4 This calls for a distinction in the numbering of the Restricted

part and the Applicants Part (e.g. addition of "AP" and "RP")

to prevent unnecessary work. See also comment on

lines17-18.

Partially accepted:








205-207, 208 2 In general, restricted part information changes cannot be

disclosed to the applicant and are included in an updated RP

submitted directly to the competent authority with a

notification to the applicant to be submitted as a variation.

Therefore, we suggest change to the sentence "To inform

the applicant and the competent authority of any significant

change in the ASMF"

Proposed change:

“to inform the Marketing Authorisation holder/Applicant of

any significant change which affects the quality of the

Active substance Marketing Authorisation holder/Applicant

and Competent Authority/EMEA of any change in the Active

Substance Master File”

Not accepted:

Not applicable.





205-207 4 See also comment on lines 159-160: there should not be a

time limit for MAVs.

Not accepted:

Not applicable.




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205-207 5 Comment: Does the one month time period in line 159

apply here as well? If so, similar comments/concern as

those listed under Lines 159-160 are valid for these lines as

well.

Proposed change: Clarify the wording so all expectations

are clear to the MA and ASMF holder.

This comment has been previously

addressed (see above)

206 1 We think clarification would be useful as to the type of

variation to be filed. We believe a Type IA variation would

be appropriate.

Not accepted:

Not applicable.





208-211 2 We are concerned that it is not explained clearly what the

process is in the case an update has been made to an ASMF

(as part of another MAA), but the MAH is not in a position to

update the dossier for their MAA in line with this change

due to eg pending MRP procedures.

Further explanation of this process is requested in this

section, along with clarification of how it is expected the

ASMF holder will provide data to the MAH and involved

NCAs/EMA (before/after implementation of the change),

and when the MAH will then be expected to update their

dossier by variation to fulfil their legal obligations.

Partially accepted:









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Proposed change:

Please expand this section to include above mentioned

procedural aspects.

208-215 2 General comment:

Implementation of ASMF changes due to on-going

registration procedures of various drug products

manufactured by various drug product manufacturers in

various countries may take several years.

Improved reporting system of ASMF changes would speed

up the process, reduce regulatory burden and

administrative work of both national authorities and

industry.

Later date of change implementation generally means

higher drug substance production costs for that period and

restricts API development.

Not accepted:

Response to comment not applicable

208 4 "cannot be changed for a certain period of time because of

other procedural provisions". This is practically impossible in

multiple customer situations where more procedures may

run at the same time with different timings.

Partially accepted:







The initiatives to improve the ASMF

procedures are being developed by the

CMD, partly in response to the scenario

where the same ASMF is licensed out in



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multiple procedures in multiple Member

States, resulting in duplication of the ASMF

assessment, multiple requests for

information, responses and divergent

updates of the ASMF,

These initiatives will aim to reduce




ASMF across Europe.

209 1 Is it the ASMF holder’s responsibility to gather the

information about applications / renewals ongoing at his

clients, and then propose an acceptable implementation

date to all ones?

Partially accepted:





















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ASMF across Europe.

211 2 The paragraph below has been removed in draft rev 3

whereas it is included in the guideline in force as well as in

draft 2. It concerns the MA Holders declaration and clarifies

what is stated in lines 212 ff.

“At the occasion of the 5-yearly renewal of a medicinal

product, MA holders are required to declare that the quality

of the product, in respect of the methods of preparation and

control, has been regularly updated by variation procedure

to take account of technical and scientific progress, and that

the product conforms with current CHMP/CVMP quality

guidelines. They will also declare that no changes have

been made to the product particulars other than those

approved by the Competent Authority/EMA.”

Proposed change:

Please reintroduce the paragraph above or remove lines

212-215.

Accepted:

The comment is endorsed and the text

amended. The proposed text has been

amended to reflect the fact that MAs

undergo a single renewal at 5 years.

211 4 Specifying an implementation date is impossible in a multi-

customer situation.

Partially accepted:












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ASMF across Europe.

212 4 It is not clear what the “above declaration” pertains to. This

paragraph probably originates from the former version of

this guideline, from which the explanatory paragraph has

been deleted

Accepted:


amended. The proposed text has been

amended to reflect the fact that MAs

undergo a single renewal at 5 years.

219

Annex 1

2 The footnotes 3 and 4 do not seem to adequately capture

the current situation.

There is no ready experience highlighting the need for

Section 3.2.S.2.4 control of critical steps and intermediates

to be part of the Applicant’s part.

It is therefore suggested to adopt the following approach:

Applicant’s part: (3); with 3) as far as the information is

relevant to the Applicant/MAH.

Restricted part: X

Proposed change:

Please amend accordingly.

Not accepted:

Not applicable.





219 In our opinion chapter 3.2.S.2 should only be submitted in Not accepted:



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the restricted Part of the DMF. This also applies for

3.2.S.2.4

Not applicable.





247-250

Annex 2

2 ASMF reference numbers are not allocated by all European

countries and are not available during first ASMF

submission.

Partially accepted:

A separate document is being prepared

regarding the EU numbering system for

ASMFs to be used by competent authorities.

This will not affect existing numbering

systems used by ASMF holders but where

relevant the comments made will be taken

into account when developing the

numbering system.

250 4 It is the aim of the CMDh group to have one ASMF number

to be used all through Europe.

Not accepted:


252

Annex 2

Template LoA

2 The inclusion to a reference to the active substance name in

the Letter of Access is an improvement.

Proposed change:

None

Not accepted:

No response applicable.

255

Annex 2:

Template LoF

2 Annex 2 requires the inclusion of the manufacturing site of

the API covered by the ASMF. However in Annex 3, when

details are required on the concerned manufacturing sites,

a foot note clarifies expectations i.e. “All companies

involved in the manufacture of the active substance,

Accepted:

The text has been deleted.



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including quality control / in process testing sites,

intermediate manufacturers, milling and sterilisation sites

should be listed in separate boxes. Brokers or supplier

details are not acceptable and should not be provided”.

Proposed change:

The various meaning of manufacturing should preferably be

clarified.

262 2 Comment:

‘Template Letter of Access’, [Planned date of submission]:

inclusion of planned date of submission of MAA or MAV

should be only mandatory for new submissions/variations

(inclusion of new supplier). In case of e.g. editorial changes

this may not be feasible;

Proposed change:

A respective footnote ‘only mandatory for new

submissions/variations (inclusion of new supplier)’ is

proposed for [Planned date of submission]

Partially accepted:





However, it is intended that the Letter of

Access is provided only with the initial

submission of the ASMF and will be valid for

subsequent updates, until revoked by the


262 4 Template Letter of Access’, [Planned date of submission]:

inclusion of planned date of submission of MAA or MAV

should be only mandatory for new submissions and

variations to include a new API supplier). In case of other

changes this is not feasible;

Proposal:

Include a footnote ‘only mandatory for new submissions

and variations to include a new API supplier '

Partially accepted:










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269

Annex 2

2 Comment:

According to Directive 2001/83/EC (p.83), active substance

manufacturer should inform the applicant in case of

changes in manufacturing process and specifications and

not for any change.

Not accepted:

This comment is not endorsed.

Other changes to the information on active

substance can be quality critical, e.g.

stability data supporting a re-test period,

and maybe required as part of other

legislation e.g. variation regulations.

Also, the statement is retained from the

previous version of the LoA.

271-275

Annex 2

Template LoA

2 Comment:

The draft guideline introduces the possibility for NCA/EMA

to exchange ASMF Assessment Reports among themselves,

regardless of the NCA/EMA being formally involved in the

concerned procedures.

This is welcome however the core text of the draft guideline

does not specifically refer to this approach nor to the

possibility of worksharing (See general comments).

Proposed change:

Please introduce in the core text of the draft guideline a

specific reference to this approach and to the possibility of

worksharing.

Accepted:


been corrected.

274 4 Please revise this paragraph in order to prevent that the

assessment reports will be shared by NCA's not

participating in any MAA.

Proposal:

Not accepted:




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Insert "where the MAA is submitted" after the word

Healthcare.

281-372

Annex 3

Template

Submission

Letter and

Administrative

Details for

documents

relating to an

ASMF

2 The Submission Letter and Administrative Details are

detailed and are an improvement.

Administrative Details strongly resemble MAA/MAV

Application forms.

Proposed change:

Please envisage to make the Administrative Details form

template available in stand-alone word format.

Accepted:

The comment is endorsed.

Word versions of Annexes 2, 3 & 4 will be

made available on the EMA website.

281 4 Any currently used country-specific administrative form (if

applicable) should be replaced by this template, a

respective explanatory note would be appreciated.

Partially accepted:

The Annex 3 Submission Letter and

Administrative Details Form has been

developed by the CMD Working Group on

ASMF procedures and its inclusion in the

note for guidance should discourage country

specific administrative forms redundant; an

explanatory note is not required.

Annex 3 2 Comment:

With regard to Annex 3: ‘Template Submission Letter and

Administrative Details for documents relating to an Active

Substance Master File’ we have the following comment: any

currently used country-specific administrative form (if

applicable) should be replaced by this template, a

respective explanatory note would be appreciated.

Partially accepted:

The Annex 3 Submission Letter and

Administrative Details Form has been

developed by the CMD Working Group on

ASMF procedures and its inclusion in the

note for guidance should discourage country

specific administrative forms redundant; an

explanatory note is not required.



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Proposed change:

299-300, 334

Annex 3

2 Comment:

ASMF reference numbers are not allocated by all European

countries and are not available during first ASMF

submission. Should EMA be added in box line 334?

Partially accepted:

A separate document is being prepared

regarding the EU numbering system for

ASMFs to be used by competent authorities.

This will not affect existing numbering

systems used by ASMF holders but where

relevant the comments made will be taken

into account when developing the

numbering system.

304 4 "Dear Sirs" should read: "Dear Madam, Sir"

Accepted:


changed

306-308 2 Comment:

An ASMF may be referred to in subsequent / multiple

submissions of drug products. In this case there is no

additional Letter of Submission but only Letter of Access.

Therefore, the list of drug products is relevant only for the

1st drug product submission and is not applicable for a

Letter of Submission. Please note that this information is

included in the letter of access. We recommend deleting

this table/ information.

In addition, Clarification needed that this form should be

submitted only upon the 1st submission of the ASMF. In

subsequent submission only LOA is sent.

Proposed change:

Partially accepted:











Details Form (Annex 3) will be provided with

the initial submission, plus response to

deficiency questions, updated, etc.



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Delete the table of products list

Clarification needed that this form should be submitted only

upon the 1st submission of the ASMF. In subsequent

submission only LOA is sent.

Therefore, this should include information on

the associated MA/MAV

308-319 3 Comment: If a Letter of Access in enclosed with the

submission letter the information requested in these lines

are superfluous. It is proposed to start with line 334

Proposed change:

Medicinal product

Allocated procedure number (H or V and as applicable)

(Intended) Submission date of the marketing authorization

application or variation (if known)

Partially accepted:














308-319 It is unclear why this information needs to be submitted.

Normally, the information required is already

incorporated in the accompanying Letter of Access.

In the case of changes, the required information needs to

be provided in the table under lines 371-372.

See also comments on 159-160: normally the ASMF is only

submitted once and further MAA use a new Letter of Access

to the same ASMF.

Partially accepted:












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308 5 Comment: Clarification requested on how to address an

unknown submission date.

Proposed change: Omit any reference to a date.

Not accepted:


Regular communication between the ASMF

holder and the MAH is strongly encouraged.

311 & 399 1 Proposed change:

Please replace “EMEA” by “EMA”.

Not accepted:

The comment is not endorsed

329-332 3 Comment: It is proposed to revise the text so the

submission of all the requested information is only

mandatory when the actual information in the

Administrative details is new or has been altered in a

variation or in response to a deficiency.

Proposed change: This Submission Letter should be used

for an Active Substance Master File to be assessed in

conjunction with a new marketing authorisation application

or variation for medicinal product for Human/Veterinary use

(if changed), using either a National or Mutual Recognition

or Decentralised or Centralised Procedure.

Partially accepted:














334 1 Would that be worth mentioning that the box “national

only” should be ticked in any case of multiple dispatch to

several countries, within national procedures (e.g.

Accepted:

The comment is endorsed and a footnote

added



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submission of a variation, by national application, to

register a new API manufacturer in all concerned

countries)?

334-335 3 Comment: It is proposed to allow updates of subsections

instead of the proposed overall version number for the AP

and the RP.

Proposed change:

Applicants part:

Version S1 [version number]/date (dd-mm-yyyy)

S2 [version number]/date (dd-mm-yyyy)






Restricted part:

Version S2.1 [version number]/date (dd-mm-yyyy)

S2.2 [version number]/date (dd-mm-yyyy)





Accepted:

The comment is endorsed but no change is

made to the text. However, separate

guidance on completing and submitting the

Annexes 2, 3, & 4 are being prepared and

these comments will be taken into account

when drafting the above document

336-337 3 Comment: The information mentioned here is duplicated

throughout the dossier and submission documentation. It is

proposed to remove these lines and request either a Letter

of Access or the Quality Overall Summary annexed to the

Not accepted:




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submission letter.

Proposed change:

ASMF-holder

Active Substance Manufacturer

Manufacturing site(s)

339 & 343 1 Comment:

If an ASMF is replaced by a CEP this will be a variation

submitted by the MA holder. It is not clear why the ASMF

holder should submit a submission letter in the context of

the replacement of an ASMF by a CEP.

Proposed change:

Deletion of “Replacement of ASMF by a Ph. Eur. CEP”,

“Copy of Ph. Eur. CEP including annexes (in case of ASMF

closing and replacement by a CEP)”

Partially accepted:

The statement has been moved to the

Withdrawal of Access letter (Annex 4). This

will not replace the MAH responsibility to

submit appropriate MAV applications.

339

Annex 3

2 Comment:

Category "Replacement of ASMF by CEP" should be omitted

from the template.

Annex 3 is submission letter for ASMF and not for CEP.

Authorised CEP is not submitted to national authorities but

only to Applicants.

Partially accepted:





339 and 343 5 If an ASMF is replaced by a CEP this will be a variation

submitted by the MA holder. It is not clear why the ASMF

holder should submit a submission letter in the context of

the replacement of an ASMF by a CEP.

Partially accepted:







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Proposed change: Deletion of “Replacement of ASMF by a

Ph. Eur. CEP”, “Copy of Ph. Eur. CEP including annexes (in

case of ASMF closing and replacement by a CEP)”

341 4 Asterisk 13 states that eCTD is mandatory for applications

in the Centralised Procedure for Human medicinal products.

Since this is a guideline on ASMFs, it needs to be clarified

that this is not required for ASMFs supporting these

applications.

Not accepted:

In the Centralised Procedure for Human

medicinal products the format requirements

applicable to marketing authorisations

applications also apply to ASMFs.

341 4 In case of an eCTD submission the history of sequences is

shown via view options for the eCTD file. Therefore a

separate sequence tracking table is not considered to be

necessary.

Proposal :

Please delete the Submission format option “History of the

sequences …”

Not accepted:


341 4 The restriction to veterinary medicinal products for CTD is

incorrect.

Proposal:

Please delete asterix 14 in submission format option “CTD”.

Not accepted:


341 4 Please add “(V) NeeS” to the list of abbreviations.

Accepted.

343-344 3 Comment: With the submitted documents there is also

mention of an ASMF section: 3.2.S.4.1. Specifications.

When this section has been updated it is part of a

submission, response or variation and is enclosed in the

updated eCTD sequence. Duplication of documentation

Accepted:

The comment is endorsed and a footnote to

state that this is not needed for eCTD or

NeeS submission has been added.



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should be avoided if possible, therefore it is proposed to

remove the sentence.

Proposed change:

A copy of the proposed ASMF holder’s active substance

specification (3.2.S.4.1 or part 2.C.1.1, as appropriate)

343-344 3 Comment: Deficiency letters contain a lot of information

most of which is not relevant to the ASMF holder or the

reviewer. It is therefore proposed to remove this request.

Proposed change:

A copy of the Deficiency letter sent by Competent Authority

/ EMA (only for submission of response documents)

Accepted:

The comment is endorsed. The text has

been amended to clarify the deficiency letter

relevant to the ASMF.

343-Footnote 17 1 It is quite odd to refer to a former version of this guideline,

when the information is presented in annex 2 of the current

version of the guideline.

Accepted:


amended.

343 2 Comment:

Footnote 17 is referred to (in relation to the Letter of Access

Annex), but the wording of the footnote seems to refer to

the wrong version of this guideline.

Proposed change:

“17 see template in annex 2 of CHPMP/QWP/227/02 Rev.13

(EMEA/CVMP/134/02 Rev. 13) Guideline on active substance

master file procedure “

Accepted:


amended.



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343

Annex 3

2 Comment:

Box in line 343 describes documents which should be part

of drug product dossier.

ASMF is submitted to authorities by drug substance

manufacturers and therefore list should be revised.

Following is submitted to authorities by API manufacturers:

- Transmittal letter

- Letter of access

- ASMF (Applicant's part, Restricted part, QoS for

Applicant's part, QoS for Restricted part)

- Responses to deficiency letters

- Revised ASMF sections

- Amendments describing changes

- Correlation tables

- Application forms (i.e. French, Swiss NA)

Not accepted:


343 4 It should be obvious that the template within this guideline

should be used for issuing a Letter of Access.

Proposal :

Rephrase asterix 17 "see Annex 2".

Accepted:

The comment is endorsed and text

amended.

347 1 Would the Applicant/MAH be authorised to receive this

table, with changes impacting the AP? It may be useful to

ensure consistency with the variation’s application form.

The Submissions Letter and Administrative

Details (Annex 3) relates to ASMF

submissions from the ASMF holder to a

NCA/EMA.

The applicant/MAH would be required to

have knowledge about the various changes

to an ASMF update in order to submit the

MAV application. The AP ToC may be useful



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in this respect; the RP ToC may contain

confidential information.

347-357 2 Comment:

It is still not clear how the EU numbering system will apply

to ASMFs which are under different stages of review across

multiple MAAs. (See general comment on the need for

different versions of a unique ASMF).

Partially accepted:








The inclusion of a table outlining present and proposed CTD

sections, and the wording “If the changes have been

previously authorised in a National or European

procedure….” suggests that different approved versions of

individual CTD sections are possible, when in fact the EU

numbering system means that only one version of each

section should be in existence at any one time in the EU. It

is requested that there is better clarification of how the EU

numbering system will allow the existence of ASMFs which

are under different stages of review across multiple MAAs.

Proposed change:

Partially accepted:



for ASMF assessment for ASMFs to be used

by competent authorities. The comments

made will be taken into account when

developing the above documents.

347 4 From line 350 we conclude that the template “Table of

Changes” is not to be part of the template submission

letter, but needs to submitted as a separate document.

Accepted:

A Word version of Annex 3 will be made

available on the EMA website. ASMF holders



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Proposal:

Please separate both templates by creating Annex 3b for

the template table.

can extract the ToC from this document so a

separate annex is not required.

352-353 2 Comment:

ASMF holder(s) might not have full overview of drug

product registrations therefore "if available" should be

added or the sentence should be omitted.

Not accepted:

The comment is not endorsed. The ASMF

holder should have full overview of the drug

product registrations, particularly for

updates, as they will have submitted LoA for

the procedures and committed to inform

applicants/MAHs of updates to the ASMF

356-357 3 Comment: It is proposed to allow updates of subsections

instead of the proposed overall version number for the AP

and the RP.

Proposed change:

ASMF holder’s RP and/or AP Version number

Subsection with ASMF holder’s version number

(CTD or NtA, as appropriate)

Partially accepted:


made to the text. However, separate

guidance on completing and submitting the

Annexes 2, 3, & 4 are being prepared and

these comments will be taken into account

when drafting the above document

373-410

Annex 4

Template

withdrawal of LoA

2 Comment:

The introduction of Annex 4 will contribute to streamline

regulatory documentation on API.

The timeframe proposed for ASMF holders is 6 months.

Although continuous relationship between ASMF holders and

MA holders should allow earlier information, it is important

to highlight that 6 months is a tight timeframe considering

one would have to find an alternative supplier, manufacture

new batches of finished product using the new API (produce

Accepted:

The comment on the timing is endorsed and

the text amended.

Separate guidance on completing and

submitting the Annexes 2, 3, & 4 are being

prepared and these comments will be taken

into account when drafting the above

document



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stability data) and have a variation filed and approved.

This could lead to supply issues of medicinal products in the

case only one ASMF is approved in a dossier (worst case

scenario). We request that this timeline be revised to

include a reference to the actual contract termination

between the ASMF holder and the MAH.

In addition, the practical consequences of LoA withdrawal

also need to be clarified:

Impact on bulk API available at the medicines

manufacturing site: can batches be produced and released

with the remaining API?

This is particularly important in situations where a single

API is registered in one MA.

What is the timeframe to remove an API supplier from an

MA (via variation)?

Proposed change:

The letter should ask for ASMF holders to detail when the

MA holders was/were informed.

The letter should also amend the last paragraph to read:

‘The aforementioned Active Substance Master File holder

also hereby confirms that they have previously informed

[Name of Marketing Authorisation Holder/Applicant] of this

decision at least 6 months before the date of this letter, i.e.

at the time of the termination of the supply contract

[dd/mm/yyyy].’

The consequences of not informing the MA holders should

be made clear in the core guidance document.



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401-403 4 This paragraph implies that the decision to withdraw the

LoA is always the ASMF holder’s. The real problem is the

applicants/MAHs who don’t tell the ASMF holder when their

applications/products have been withdrawn. Therefore it

should be made clear that applicants/MAHs are obligated to

do this.

Partially accepted:


made to the text. Regular two-way

communication between ASMF holder and

MAH is encouraged.

402-403 4 Is 6 months a requirement or a recommendation?

If the MAA holder agrees to have the LoA withdrawn

sooner,

Is there any reason to wait 6 months?

Until now there was no such procedure, which means that

there is a huge backlog. In practice, some applicants may

not even exist anymore. How should this be handled?

Proposal :

‘...of this decision at least 6 months before the date of this

letter or a mutual agreement on this withdrawal exists."

Accepted:


the text amended.

402-403 5 Comment: Is 6 months a requirement or a

recommendation? If the MAA Holder agrees to have the

ASMF withdrawn sooner, is there is reason to wait 6

months?

Proposed change: “… of this decision at least a

recommended 6 months before the date of this letter.”

Accepted:


the text amended.

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